Our group has been pursuing the studies of the role of cellular receptors in inflammatory responses and tumor progression.We are especially interested in formyl peptide receptors that interact with bacterial and host-derived chemotactic peptids. In humans, there are three functional fMLF receptors, FPR, FPRL1, and FPRL2. Mice with disrupted FPR gene showed reduced resistance to bacterial infection, suggesting this receptor may be involved in host defense against microbial infection. Recently our laboratory and other laboratories identified a number of novel chemotactic agonists for both FPR and FPRL1. These agonists include small peptides derived from peptide libraries, peptide domains derived from HIV-1 envelope proteins, and more importantly, peptide agonists associated with tumor as well as inflammatory and neurodegenerative diseases. These findings expanded the functional scope of formylpeptide receptors. We have identified a neutrophil granule protein Cathepsin G (CaG), which is bactericidal, cleaves a number of proteins, promotes antibody responses when injected in mice, and chemoattracts human granulocytes and monocytes, as a novel chemotatic agonist for the receptor FPR. This finding provides important molecular basis for many biological activities of CaG and will assist in the design of agents that promote host defense based on the structure and function of CaG. We also studied the role of formalpeptide receptor FPR in promoting tumor progression. We found that highly malignant human glioma cells, including those from established tumor cell lines and primary glioma specimens, express FPR. FPR mediates the migration of high malignant human glioma cells in response to ligands contained in the extracts of necrotic tumor tissues. Activated FPR also promotes tumor cell growth and production of VEGF that is crucial for formation of new blood vessels in tumors. We utilized short RNA-interference to delete FPR from glioma cells, and such tumor cells exhibited greatly reduced capacity to form deadly tumors in nude mice, as compared with tumor cells that express FPR. Thus, FPR may act as an important contributor to the aggressive behavior of highly malignant human glioma cells thus it can be considered as a target for the development of anti-glioma therapeutics.We have revealed a potentially important role of another formylpeptide receptor FPRL1 in the inflammation and neurodegeneration in Alzheimer's disease, which is characterized by over-production of Abeta42 peptides in the brain in association with accumulation and activation of brain macrophages (microglia). We found that FPRL1 not only mediates the chemotactic activity of Abeta42 but also promotes the internalization and subsequent intracellular aggregation of Abeta peptides in macrophages. The interaction of FPRL1 with Abeta42, but not with non-amyloidogenic peptide agonists in macrophages and neuronal cells increased apoptosis of the cells. The mouse counterpart of FPRL1, namely mFPR2, also mediates the chemotaxis and super oxide release in myeloid cell stimulated by Abeta42 and the expression of this receptor was enhanced in mouse primary microglial cells by proinflammatory signals such as ligands by Toll-like receptors. Despite the progressive neurodegenration in AD, the occipital lobes of the patient brains are rarely affected. This has led to the identification of a gene coding for a small neuroprotective polypeptide Humanin (HN). In studies of the mechanisms of HN in neuroprotection, we found that HN shares the formylpeptide receptor FPRL1 and mouse mFPR2 with Abeta42. By sharing FPRL1, HN reduces the aggregation of Abeta42 in macrophages and its toxicity for neuronal cells. These findings provide the rationale for our proposed studies using mouse models of Alzheimer's disease to further elucidate the contribution of FPRL1 and mFPR2 to the pathogenesis of Alzheimer's disease.